A population pharmacokinetic model of remdesivir and its major metabolites based on published mean values from healthy subjects

Abstract

Remdesivir is a direct-acting anti-viral agent. It was originally evaluated against filoviruses. However, during the COVID-19 pandemic, it was investigated due to its anti-viral activities against (SARS-CoV-2) virus. Therefore remdesivir received conditional approval for treatment of patients with severe coronavirus disease. Yet, its pharmacokinetic properties are inadequately understood. This report describes the population pharmacokinetics of remdesivir and its two plasma-detectable metabolites (GS-704277 and GS-441524) in healthy volunteers. The data was extracted from published phase I single escalating and multiple i.v remdesivir dose studies conducted by the manufacturer. The model was developed by standard methods using non-linear mixed effect modeling. Also, a series of simulations were carried out to test suggested clinical doses. The model describes the distribution of remdesivir and each of its metabolites by respective two compartments with sequential metabolism between moieties, and elimination from central compartments. As individual data were not available, only inter-cohort variability could be assessed. The estimated point estimates for central (and peripheral) volumes of distribution for remdesivir, GS-704277, and GS-441524 were 4.89 L (46.5 L), 96.4 L (8.64 L), and 26.2 L (66.2 L), respectively. The estimated elimination clearances of remdesivir, GS704277, and GS-441524 reached 18.1 L/h, 36.9 L/h, and 4.74 L/h, respectively. The developed model described the data well. Simulations of clinically approved doses showed that GS-441524 concentrations in plasma exceeded the reported EC50 values during the complete duration of treatment. Nonetheless, further studies are needed to explore the pharmacokinetics of remdesivir and its relationship to clinical efficacy, and the present model may serve as a useful starting point for additional evaluations.